Presentation made July 28, 2016 at the live webinar hosted by the Schizophrenia Research Forum and titled Studying Psychosis in 22q11 Deletion Syndrome. Video recording and additional materials at http://www.schizophreniaforum.org/for/live/detail.asp?liveID=100

1. 22q11.2 deletion syndrome
(22q11.2DS)
The first clinically identifiable molecular
cause of schizophrenia
Anne S. Bassett, MD, FRCPC
Canada Research Chair in Schizophrenia Genetics and Genomic Disorders
Dalglish Chair in 22q11.2 Deletion Syndrome
Senior Scientist, Toronto General Research Institute
Senior Scientist, Campbell Family Mental Health Research Institute
Director, Dalglish Family 22q Clinic, Toronto General Hospital

2. 22q11.2 Deletion Syndrome (22q11.2DS)
• Known clinical condition since the 1960s
– Variety of names, now under one molecular umbrella
• Targeted clinical testing (FISH) available since 1994
• Clinical testing: now genome-wide microarray or MLPA
• Known association with schizophrenia since 1992-94
(Shprintzen, 1992; Pulver et al., 1994; Chow et al., 1994)
– 1 in every 4 individuals with 22q11.2DS develops schizophrenia
• Not found in large control samples
• Unbiased prevalence studies show deletion 22q11.2 in
an estimated 1 in 100-200 patients with schizophrenia
(Horowitz et al., 2005; Bassett et al., 2010)
• The first true molecular genetic subtype of schizophrenia

3. Am J Psychiatry 2010; 167:899–914
Structural genomic changes
Copy number variation
(CNV)
Broader context
Genome-wide CNV – discovery
(Iafrate et al., 2004; Sebat et al., 2004;
Redon et al., 2006)
Associated with schizophrenia
Rare
Often recurrent (*)
Loss (deletion) or
Gain (duplication)
Some have high penetrance
Clinically pathogenic CNVs
Up to 5% of schizophrenia
(Costain et al., Human Molecular
Genetics 22:4485-4501, 2013)
*

4. 22q11.2 deletion region
Deletions
~90%
~5%
Segmental duplications (LCRs)
22q11.2 deletion syndrome. Nat. Rev. Dis. Primers 2015; doi:10.1038/nrdp.2015.71
Non-allelic homologous recombination (NAHR) between misaligned low copy repeats
(LCRs) during gametogenesis underlies recurrent rearrangements
Slight excess of maternal origin
No maternal or paternal age effect (Bassett et al., 2008; Delio et al., 2013)

5. 22q11.2 Deletion Syndrome (22q11.2DS)
• Hemizygous chromosome 22q11.2 deletion
• Most common microdeletion syndrome in humans
– Usual prevalence estimate: ~1/2000-1/4000 live births
– Prenatal studies prevalence of typical 22q11.2 deletions
In 3,822 karyotypically normal pregnancies (Wapner et al., 2012):
– 1/347 pregnancies had 22q11.2 deletions
In 9,648 pregnancies in a multicentre study (Grati et al., 2015):
– 1/992 pregnancies had 22q11.2 deletions
• The true live birth prevalence remains to be determined
• Most are de novo (spontaneous) genetic changes
• Only ~ 5-10% are found to be inherited from a parent
• Congenital and later onset features, variable expression
• Clinically recognizable though under-recognized

6. Neuropsychiatric expression of 22q11.2DS
• Neonatal seizures (usually hypocalcemic)
• Developmental delay and intellectual disabilities
• Autism spectrum features and disorder
• Attention deficit disorder
• Recurrent seizures / epilepsy
• Mood and anxiety disorders
• Schizophrenia and other psychotic disorders
• Neurodegenerative disorders (Parkinson disease)
Butcher et al. JAMA Neurology 70:1359-1366, 2013
Bassett et al. AJMG 138A:307-313, 2005; Fung et al. Am J Psychiatry 167:998, 2010; Schneider et al. Am J
Psychiatry 171:627-639, 2014; McDonald-McGinn et al. Nature Reviews Disease Primers 1:15071, 2015

7. The Schizophrenia Phenotype in
22q11 Deletion Syndrome (22q11DS)
American Journal of Psychiatry, 160:1580-86, 2003
Is it Schizophrenia?
Is the schizophrenia in 22q11DS similar to that of other
forms of schizophrenia?
Yes
Median age at onset ~ 21 y
Meets DSM criteria, same signs and symptoms as for
heterogeneous schizophrenia samples
Could the clinical features of schizophrenia be used to
identify 22q11.2DS patients?
No (rely on physical features/developmental history for
index of suspicion)

8. • Clinical practice guidelines (J Peds, 2011; GIM, 2015)
• Standard management for each individual condition
– Personalized for 22q11.2DS
– Clozapine, e.g. (Butcher et al., British J Psychiatry, 206:484-491, 2015)
• Targeted investigations and monitoring
• Early diagnosis of treatable psychiatric illness
• Family/caregiver involvement (Costain et al., JIDR 56:641-651, 2012)
• Genetic counselling (Costain et al., JMG 48:819-824, 2011)
– Reproductive: 50% risk of transmitting 22q11.2 deletion
– Associated psychiatric and medical conditions, reduced longevity
Personalized care for 22q11.2DS

9. • 90 genes
• 46 protein-coding genes
• Most are expressed in brain
• Many, but not all, have
decreased expression with
hemizygosity
− DGCR8 is one of the key
genes in the region
− Conserved; haploinsufficient
− Encodes a protein (“Pasha”)
involved in miRNA biogenesis
− miRNAs act as buffers at
transcription and translation
of proteins genome-wide
Genes in the 22q11.2 deletion region

10. Possible mechanism of DGCR8
haploinsufficiency in 22q11.2DS
Hypothesis & Theory ARTICLE
Front. Genet., 13 December 2012 | doi: 10.3389/fgene.2012.00291
miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome
Linda M. Brzustowicz1,2* and Anne S. Bassett3,4,5

11. 22q11.2DS whole genome sequencing pilot study
of schizophrenia - Toronto
The
Centre for
Applied
Genomics
Extreme phenotype approach – within 22q11.2DS
Standard pipeline focusing on high quality rare variants +
Gene-set analysis that
Prioritized genes likely to be involved in brain function
Restricted to those affected by DGCR8 haploinsufficiency
= Promising strategy with notable effect sizes

12. Under way...
• International consortium – IBBC (NIMH)
– Whole genome sequencing and genome-wide
microarray to delineate sequence and structural
variation contributing to expression of schizophrenia
• Promise of prospective studies, Rx trials
• Animal and cellular models to investigate
mechanisms and help develop new treatments
• Further elucidation of natural history, long term
outcome and management
• Epidemiology - newborn screening